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Primeur weekly 2016-10-10

Exascale supercomputing

The incredible shrinking particle accelerator ...

Brookhaven Lab to play major role in 2 DOE exascale computing application projects ...

Quantum computing

More stable qubits in perfectly normal silicon ...

Focus on Europe

RSC supercomputers go West ...

Hardware

Allinea tools play vital role in advancing computational research at the VSC, Austria's largest HPC facility ...

Smallest transistor ever ...

Turning to the brain to reboot computing ...

Complex materials can self-organize into circuits, may form basis for multifunction chips ...

Wireless data centre on a chip aims to cut energy use ...

Adapteva announces 28nm 64-core Epiphany-IV microprocessor chip ...

SGI introduces unique scale-out solution for SAP HANA that protects investments when moving to real-time business ...

Applications

Clemson University scientists receive $1.8 million grant to combat Type 2 diabetes ...

Climate change intensifies night-time storms over Lake Victoria ...

Computer simulations explore how Alzheimer's disease starts ...

Rice University lab explores cement's crystalline nature to boost concrete performance ...

Rice University researchers say 2D boron may be best for flexible electronics ...

Large animals, such as the imperious African elephant, most vulnerable to impact of human expansion ...

Computer simulation finds dangerous molecule activity for ageing ...

Tornadogenesis ...

As hurricane heads up coast, a RENCI supercomputer swings into action ...

New drug candidate may reduce deficits in Parkinson's disease ...

XSEDE allocations awarded to 155 research teams across U.S. ...

OSC part of NSF-funded consortium for advancing research computing practices ...

NCSA awarded NSF grant to expand computational science education in food, energy, and water ...

Crosstalk analysis of biological networks for improved pathway annotation ...

The Cloud

Nimbix collaborates with IBM and NVIDIA to launch powerful GPU Cloud offering ...

New drug candidate may reduce deficits in Parkinson's disease


Interaction of the compound (coloured by atoms: green-carbon, red-oxygen, blue-nitrogen) with alpha-synuclein (brown ribbon with colour by atoms side chains). Igor Tsigelny, UC San Diego.
5 Oct 2016 San Diego - An international team led by University of California San Diego researchers has employed a novel computational approach to design and create a new compound that in laboratory studies has reduced deficits and neurodegenerative symptoms that underlie Parkinson's disease.

In a study published in the September 27 Advance Access issue ofBrain, the researchers describe how their compound, dubbed NPT100-18A, prevents the binding and accumulation of alpha-synuclein or α-syn in neuronal membranes, now considered a hallmark of Parkinson’s disease and a related disorder called dementia with Lewy bodies.

"We've demonstrated a novel computational approach to design potential therapies for Parkinson's disease and related disorders", stated the study's co-first author Igor Tsigelny, a research scientist with the San Diego Supercomputer Center (SDSC) at UC San Diego, as well as the UC San Diego Moores Cancer Center and Department of Neurosciences.

Added Eliezer Masliah, the study's principal investigator and former professor in UC San Diego School of Medicine's Department of Neurosciences: "It's a first step, but we believe it's a big step."

Parkinson's disease, which affects more than 10 million people worldwide, is characterized by impairment or deterioration of neurons in the area of the brain known as the substantia nigra. The disease typically occurs in people over the age of 60, with symptoms of shaking, rigidity, difficulty in walking, generally developing slowly over time and sometimes followed later by impairment in behaviour and thought processes.

Since most symptoms of Parkinson's disease are triggered by a lack of dopamine in the brain, many medications are aimed at either temporarily replenishing dopamine or mimicking the action of this brain chemical. Unfortunately, current drugs have only a limited impact on long-term neurological deficits and mortality.

For this reason, scientists have begun to focus their efforts on α-syn's role in the disease, based largely on computer modelling describing how mutant forms of this protein penetrate and coil in cell membranes, and then aggregate in a matter of nanoseconds into dangerous ring structures that open pores to toxic ions that ultimately destroy neurons. The modeling has been supported by electron microscopy showing how damaged neurons in Parkinson’s patients are riddled with these ring structures.

Following this discovery in 2012, UC San Diego researchers began an intense search to identify drug candidates that could block the early formation of ring structures. Specifically, the researchers homed in on "hot spots" that block the binding of two α-syn proteins, or dimers.

"Our thinking was that disrupting the formation of membrane-embedded dimers at this early intervention point could reverse the effects of α-syn on synaptic function at a stage before irreversible neurodegenerative processes have been initiated", stated Eliezer Masliah, now with the National Institutes of Health (NIH).

But the hunt proved highly complex, owing largely to the nature of the unstructured state of α-syn, sometimes referred to as a "chameleon" that constantly shifts its shape, somewhat like a slinky that's bobbing and weaving on top of an earthquake epicenter.

"Our biggest hurdle was that α-syn doesn't have any stable conformation", stated Igor Tsigelny. "So long simulations were needed to define a huge set of possible conformations to find clusters of possible compounds that would work."

Enter several supercomputers - including Trestles, Gordon, and the Triton Shared Computing Cluster, all based at SDSC; and Blue Gene, with the Argonne National Laboratory - that performed molecular dynamic simulations of in silico structures that would displace α-syn from cell membranes.

Based on these simulations, other members of the research team, including Wolfgang Wrasidlo, executive director of medicinal chemistry at Neuropore Therapeutics in San Diego, synthesized a library of 34 potential compounds that targeted the "hot spot" where pairs of α-syn proteins bind, merge, and aggregate in the cell membrane, an early step in the formation of toxic rings and ultimate death of a neuron. Of these drug candidates, the researchers identified one compound - NPT100-18A - as the most promising.

"Essentially, this compound mimics the protein's amino acids in the place where two α-synucleins come into contact, thus preventing the binding of the second protein", stated Wolfgang Wrasidlo, previously with UC San Diego Moores Cancer Center, and the study's first author.

Subsequent electron microscopy imaging by researchers at the University of Vienna demonstrated that the new compound reduced the formation of α-syn clusters in cell membranes. Further studies with "transgenic" mouse models prone to Parkinson’s disease, both at UC San Diego and UCLA, concluded that the compound improved behavioral deficits and neurodegeneration. Within an hour after it was administered, imaging studies in these mice further showed that the compound reduced accumulation of α-syn in cortical synapses.

"Specifically targeting the α-synuclein structure that is stabilized in cell membranes also allows for a more specific molecularly targeted drug design", added Eliezer Masliah.

Though highly encouraging, the researchers caution that the compound needs to be refined before clinical trials can be launched in the future.

Also contributing to the study, titled "A De Novo Compound Targeting Alpha-Synuclein Improves Deficits in Models of Parkinson's Disease", were Edward Rockenstein, Simona Eleuteri, Valentina Kouznetsova, Brian Spencer, Paula Desplats, Tania Gonzalez-Ruelas, Margaritha Trejo, and Cassia Overk, all from UC San Diego; Garima Dutta, Chunni Zhu, and Marie-Francoise, all from UCLA; Thomas Schwartz, Karin Ledolter and Robert Konrat, all from the University of Vienna; Diana Price, Douglas Bonhaus, Amy Paulino and Dieter Meier, all from Neuropore, based in San Diego; Stefan Winter and Herbert Moessler, from EVER Neuropharma, based in Austria; and Age Skjevik, from the University of Bergen in Norway.

Funding for the research came from NIH grant AG18440, The Michael J. Fox Foundation for Parkinson's Research, and Neuropore Therapies.

Source: University of California - San Diego

Back to Table of contents

Primeur weekly 2016-10-10

Exascale supercomputing

The incredible shrinking particle accelerator ...

Brookhaven Lab to play major role in 2 DOE exascale computing application projects ...

Quantum computing

More stable qubits in perfectly normal silicon ...

Focus on Europe

RSC supercomputers go West ...

Hardware

Allinea tools play vital role in advancing computational research at the VSC, Austria's largest HPC facility ...

Smallest transistor ever ...

Turning to the brain to reboot computing ...

Complex materials can self-organize into circuits, may form basis for multifunction chips ...

Wireless data centre on a chip aims to cut energy use ...

Adapteva announces 28nm 64-core Epiphany-IV microprocessor chip ...

SGI introduces unique scale-out solution for SAP HANA that protects investments when moving to real-time business ...

Applications

Clemson University scientists receive $1.8 million grant to combat Type 2 diabetes ...

Climate change intensifies night-time storms over Lake Victoria ...

Computer simulations explore how Alzheimer's disease starts ...

Rice University lab explores cement's crystalline nature to boost concrete performance ...

Rice University researchers say 2D boron may be best for flexible electronics ...

Large animals, such as the imperious African elephant, most vulnerable to impact of human expansion ...

Computer simulation finds dangerous molecule activity for ageing ...

Tornadogenesis ...

As hurricane heads up coast, a RENCI supercomputer swings into action ...

New drug candidate may reduce deficits in Parkinson's disease ...

XSEDE allocations awarded to 155 research teams across U.S. ...

OSC part of NSF-funded consortium for advancing research computing practices ...

NCSA awarded NSF grant to expand computational science education in food, energy, and water ...

Crosstalk analysis of biological networks for improved pathway annotation ...

The Cloud

Nimbix collaborates with IBM and NVIDIA to launch powerful GPU Cloud offering ...